Squamous cell carcinomas of the head and neck (SCCHN) generally overexpress epidermal growth factor receptors (EGFR) that have been linked to poor prognosis, treatment failure, and shortened survival. Protein kinase C enzymes (PKCs) have also been implicated in growth control, particularly as mediators of EGF signaling. Recently, we have demonstrated that the atypical protein kinase C isoform, PKC zeta, is necessary for EGF induced MAPK activation in head and neck cancer cell lines. PKC zeta has also been implicated in activation of p70 S6 kinase and the survival factor Nuclear Factor kappa B (NF-kappaB), and we have shown that inhibition of PKC zeta promotes apoptosis in head and neck tumor cells. Finally, we have shown that general inhibitors of classic and novel PKCs are cytotoxic to SCCHNs in vitro and in vivo, but the specific PKC isoforms responsible have not been identified. The present proposal seeks to identify the PKC isoforms that regulate signaling pathways that lead to SCCHN growth and survival, and to determine the potential efficacy of PKC inhibitors as therapeutic agents for the treatment of SCCHN. Specifically, we plan to: 1) Determine the nature of PKC expression in human tumor and normal tissues collected during clinical trials in squamous cell carcinoma of the head and neck; 2) Characterize the role of PKC isozymes in EGF and serum stimulation of head and neck tumor cells; 3) Test the effect of PKC inhibitors on apoptosis of head and neck tumor cells either alone or in combination with radiation, EGFR inhibitors, or TNF-alpha; and 4) Determine the effect of PKC targeted agents on head and neck cancer in vivo.